MX2014012859A

MX2014012859A - Pharmaceutical composition comprising (1r,4r)-6'-fluoro-n,n-dimet hyl-4-phenyl-4',9'-dihydro-3'h-spiro[cyclohexane-1,1'-pyrano [3,4,b]indol]-4-amine and antidepressants.

Info

Publication number: MX2014012859A
Application number: MX2014012859A
Authority: MX
Inventors: Klaus Linz; Thomas Christoph; Stefanie Frosch
Original assignee: Grünenthal GmbH
Priority date: 2012-05-18
Filing date: 2013-05-16
Publication date: 2015-01-19
Also published as: HRP20171922T1; HUE037746T2; RS56856B1; US20130310385A1; PL2849744T3; IL235657B; US20170065560A1; HK1204944A1; JP2015520154A; EA201401269A1; SI2849744T1; EP2849744B1; EP2849744A1; BR112014028562A2; PT2849744T; EA027268B1; DK2849744T3; WO2013170965A1; CA2873634A1; NO2849744T3

Abstract

The invention relates to a pharmaceutical composition comprising a first pharmacologically active ingredient selected from (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro [cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine and the physiologically acceptable salts thereof, and a second pharmacologically active ingredient which is an antidepressant.

Description

PHARMACEUTICAL COMPOSITION COMPRISING (IR, 4R) -6 '-FLUORO N, N-DIMETHYL-4-PHENYL-4 ', 9'-DIHYDRO-3'H-ESPIRO [CYCLOHEXAN-1,1'-PYRANO [3, 4, B] INDOL] -4-AMINE AND ANTIDEPRESSANTS FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition comprising a first pharmacologically active ingredient selected from (Ir, 4 r) -6 '-fluoro-N, N-dimethyl-4-phenyl-4', 9 '-dihydro-3' H -spiro [cyclohexan-1, 1'-pyrano [3,4, b] indole] -4-amine and the physiologically acceptable salts thereof, and a second pharmacologically active ingredient which is an antidepressant.

BACKGROUND OF THE INVENTION (Ir, 4 r) -6 '-fluoro-N, N-dimethyl-4-phenyl-4', 9 '-dihydro-3' H-spiro [cyclohexane-1,1 '-piran [3, 4, b ] indole] -4-amine and its isiologically acceptable salts as well as methods for its preparation are well known, for example, from O2004 / 043967 and WO2008 / 040481. The compounds exhibit analgesic properties and are particularly suitable for the treatment of acute, visceral, neuropathic or chronic (nociceptive) pain.

The term antidepressant, which is known to a person skilled in the art, is proposed to include all substances listed in the Chemical classification.

Therapeutic Anatomical (ATC) under [N06A] as used by the WHO for the classification of pharmaceutically active ingredients.

Antidepressants are used primarily for the treatment of mood disorders (affective disorders) but may also be effective in the treatment of anxiety, obsessive-compulsive disorders, eating disorders, insomnia, post-traumatic stress disorder and chronic pain.

Although both classes of substances mentioned above are therapeutically effective, side effects may occur, especially with prolonged use or when administered in high dosages.

It is additionally known that specific combinations of pharmacologically active compounds exert supra-additive (synergistic) therapeutic effects with their administration. An advantage of these special cases is that the total dose and as a consequence the risk of unwanted side effects can be reduced.

In a further aspect, two pharmacologically active compounds that exert a synergistic effect can be combined in a single pharmaceutical dosage form, for example a tablet, thereby increasing patient compliance.

DETAILED DESCRIPTION OF THE INVENTION It is an object of the present invention to provide pharmaceutical compositions having advantages compared to prior art pharmaceutical compositions. In particular, the pharmaceutical compositions should provide fast therapeutic effects, but they should also have high tolerability, good compliance and safety.

This object has been achieved by the subject matter of the patent claims.

Surprisingly it has been found that a pharmaceutical composition comprising (Ir, 4r) -6 '-fluoro-N, -dimethyl-4-phenyl-,' -dihydro-3'H-spiro [cyclohexane-1'-1-pyran [3, 4, b] indole] -4-amine and an antidepressant drug is useful for the treatment of pain, especially chronic pain, in particular neuropathic pain.

Furthermore, it has surprisingly been found that the composition exhibits a synergistic therapeutic effect with its administration. Therefore, the total administered dose can be decreased, so that fewer unwanted side effects will occur.

A first aspect of the invention relates to a pharmaceutical composition comprising: (a) A first pharmacologically active ingredient selected from (Ir, 4r) -6 '-fluoro-N, -dimethyl-4-phenyl- ', 9' -dihydro-3 'H-spiro [cyclohexan-1, 1' -pyrano [3,4, b] -indol] -4-amine and the physiologically acceptable salts thereof, and (b) A second pharmacologically active ingredient that is an antidepressant.

The pharmaceutical composition according to the invention comprises a first pharmacologically active ingredient selected from (lr, 4r) -6'-fluoro-N, N-dimethyl-4-phenyl- ', 9'-dihydro-3'H-spiro- [cyclohexan-1, 1'-pyran [3,4, b] indole] -4-amine and the physiologically acceptable salts thereof.

For the purpose of the specification, (lr, 4r) -6 '-fluoro-N, N-dimeti1-4-phenyl-4', 9 '-dihydro-3' H-spiro- [cyclohexan-1, 1 '- pyran [3, 4, b] indole] -4-amine is the compound according to formula (I) which can also be referred to as 1-, 1- (3-dimethylamino-3-phenylpentamethylene) -6-fluoro-l , 3, 4, 9-tetrahydropyran [3,4-b] indole (trans) (i) The definition of the first pharmacologically active ingredient includes (Ir, 4r) -6 '-fluoro-N, - dimethyl-4-phenyl-4 ', 9'-dihydro-3'H-spiro [cyclohexane-1,1'-pyrano [3,4] indole] -4-amine in the form of the free base, i.e. compound according to formula (I), in any possible form including solvates, co-crystals and polymorphs, and their physiologically acceptable salts, in particular the acid addition salts and the corresponding solvates, co-crystals and polymorphs.

The pharmacologically active ingredient (lr, 4r) -6 '-fluoro-N, N-dimethyl-4-phenyl-4', 9'-dihydro-3 'H-spiro- [cyclohexan-1,1'-pyran [3 , 4, b] indole] -4-amine may be present in the pharmaceutical composition according to the invention in the form of a physiologically acceptable salt, preferably an acid addition salt, whereby any suitable acid capable of forming such addition salt.

The conversion of (Ir, 4 r) -6 '-fluoro-N, N-dimethyl-4-phenyl-4', 9 '-dihydro-3' H-spiro [cyclohexane-1,1 '-pirano- [3, 4, b] indole] -4-amine in a corresponding addition salt, for example, via reaction with a suitable acid can be carried out in a manner well known to those skilled in the art. Suitable acids include but are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, acid citric acid, glutamic acid and / or aspartic acid. The formation of the salt is preferably carried out in a solvent, for example, diethyl ether, diisopropyl ether, alkyl acetates, acetone and / or 2-butanone. On the other hand, the trimethylchlorosilane in aqueous solution is also suitable for the preparation of the hydrochlorides.

In a preferred embodiment, the first pharmacologically active ingredient is (Ir, 4 r) -6 '-fluoro-N, N-dimethyl-4-phenyl-4', 9 '-dihydro-3' H-spiro [cyclohexan-1, 1 '-pyrano- [3, 4, b] indol] -4-amine in the form of the free base, ie the compound according to formula (I).

In another preferred embodiment, the first pharmacologically active ingredient is (Ir, 4 r) -6 '-fluoro-N, N-dimethyl-4-phenyl-', 9 '-dihydro-3' H-spiro- [cyclohexan-1, 1'-pyran [3,4-b] indole] -4-amine in the form of a physiologically acceptable acid addition salt, in particular the hydrochloride, hemicitrate or maleate salt.

Unless explicitly stated otherwise, all quantities of the first pharmacologically active ingredient specified in the following are given according to the corresponding amount of (lr, 4r) -6 '-fluoro-N, N-dimethyl-4- phenyl- ', 9'-dihydro-3'H-spiro- [cyclohexan-1,1'-pyran [3,4, b] indole] -4-amine in the form of the free base, ie the compound of conformity with formula (I).

The pharmaceutical composition according to the invention comprises a second pharmacologically active ingredient which is an antidepressant.

The definition of the second pharmacologically active ingredient includes antidepressants in any possible form, including any enantiomers, if applicable, the solvates, prodrugs, co-crystals and polymorphs, and their physiologically acceptable salts, in particular the acid addition salts and solvates, co-crystals and corresponding polymorphs.

Preferred antidepressants according to the invention can be transformed into the corresponding acid addition salts as well as the corresponding metal salts. This can be done in a manner well known to those skilled in the art, for example via reaction with a suitable acid or base as well as a metal salt. Suitable acids include but are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and / or aspartic acid. On the other hand, the trimethylchlorosilane in aqueous solution is also suitable for the preparation of the hydrochlorides. The bases Suitable include but are not limited to the hydroxides of sodium, potassium, calcium and / or magnesium. Suitable metal salts include but are not limited to alkali salts such as phosphate, sulfate, methanesulfonate, formate, acetate, oxalate, succinate, tartrate, mandelate, fumarate, lactate, citrate, glutamate, aspartate and / or sodium, potassium or lithium, as well as the alkali metal salts, in particular the magnesium and calcium salts, including their salts of phosphate, sulfate, methanesulfonate, formate, acetate, oxalate, succinate, tartrate, mandelate, fumarate, lactate, citrate, glutamate, aspartate and / or silyles. The formation of the salt is preferably carried out in a solvent, for example diethyl ether, diisopropyl ether, alkyl acetates, acetone and / or 2-butanone.

As prodrugs of antidepressants, amides are particularly preferred. Suitable methods for selecting and preparing a prodrug of a given substance are described, for example in "Textbook of Drug Design and Discovery, 3rd edition, 2002, chapter 14, pages 410-458, Editors: Krogsgaard-Larsen et al., Taylor and Francis. " In a preferred embodiment, the second pharmacologically active ingredient is an inhibitor selective serotonin reuptake.

In another preferred embodiment, the second pharmacologically active ingredient is a selective serotonin reuptake inhibitor selected from the group consisting of zimeldine, fluoxetine, citalopram, paroxetine, sertraline, alaproclate, fluvoxamine, etoperidone, escitalopram and the physiologically acceptable salts thereof. .

In yet another preferred embodiment, the second pharmacologically active ingredient is a non-selective monoamine reuptake inhibitor.

In yet another preferred embodiment, the second pharmacologically active ingredient is a non-selective monoamine reuptake inhibitor selected from the group consisting of desipramine, imipramine, imipramine oxide, clomipramine, opipramol, trimipramine, lofepramine, dibenzepine, amitriptyline, nortriptyline, protriptyline. , doxepin, iprindol, melitracene, butryptilene, dosulepine, amoxapine, dimethacrine, amineptine, maprotiline, quinupramine and the physiologically acceptable salts thereof.

In a further preferred embodiment, the second pharmacologically active ingredient is selected from the group consisting of oxitriptan, tryptophan, mianserin, nomifensin, trazodone, nefazodone, minaprine, bifemelan, viloxazine, oxaflozan, mirtazapine, bupropion, medifoxamine, thianeptine, pivagabine, venlafaxine, milnacipran, reboxetine, gepirone, duloxetine, agomelatine, desvenlafaxine, vilazodone and the physiologically acceptable salts thereof, as well as Hyperici herba.

Unless explicitly stated otherwise, all amounts of the second pharmacologically active ingredient specified in the following are given according to the corresponding amount of the free compound.

In a preferred embodiment, the second pharmacologically active ingredient is an antidepressant in the form of the free compound.

In another preferred embodiment, the second pharmacologically active ingredient is an antidepressant in the form of its hydrochloride addition salt.

In a preferred embodiment, the second pharmacologically active ingredient is duloxetine.

In another preferred embodiment, the second pharmacologically active ingredient is (S) -duloxetine.

In still another preferred embodiment, the second pharmacologically active ingredient is reboxetine.

In a preferred embodiment, the first pharmacologically active ingredient is (Ir, r) -6 '-fluoro-N, N-dimethyl-4-phenyl-4', 9'-dihydro-3'H-spiro [cyclohexan-1, 1' - pyrano- [3, 4, b] indole] -4-amine in the form of the free base, ie, the compound according to formula (I), and the second pharmacologically active ingredient is an antidepressant.

In another preferred embodiment, the first pharmacologically active ingredient is (lr, 4r) -6'-fluoro-N, N-dimethyl-4-phenyl-4 ', 9'-dihydro-3'H-spiro- [cyclohexan-1 , 1'-pyran [3, 4, b] indole] -4-amine in the form of the free base, ie the compound according to the formula (I), and the second pharmacologically active ingredient is an antidepressant in the form of the respective hydrochloride addition salt.

In still another preferred embodiment, the first pharmacologically active ingredient is (lr, 4r) -6'-fluoro-N, N-dimethyl-4-phenyl-4 ', 9'-dihydro-3'H-spiro- [cyclohexan- 1,1 '-pyrano [3,, b] indole] -amine in the form of the free base, ie the compound according to formula (I), and the second pharmacologically active ingredient is duloxetine, preferably in the form of free compound In yet another preferred embodiment, the first pharmacologically active ingredient is (lr, 4r) -6'-fluoro-N, N-dimethyl-1-phenyl-, 9'-dihydro-3'H-spirolacyclohexan-1, 1'- pyrano [3, 4, b] indole] -4 -amine in the form of the free base, ie the compound according to formula (I), and the second pharmacologically active ingredient is duloxetine, preferably in the form of the hydrochloride addition salt.

In a further preferred embodiment, the first pharmacologically active ingredient is (lr, 4r) -6'-fluoro-N, N-dimethyl-4-phenyl-4 ', 9'-dihydro-3'H-spiro- [cyclohexan- 1,1 '-pyrano [3,4] b) indole] -4-amine in the form of a physiologically acceptable acid addition salt, in particular the hydrochloride, hemicitrate or maleate salt, and the second pharmacologically active ingredient is duloxetine, preferably in the form of the free compound.

In still a further preferred embodiment, the first pharmacologically active ingredient is (lr, 4r) -6 '-fluoro-N, -dimethyl-4-phenyl-4', 9'-dihydro-3'H-spiro- [cyclohexan- 1,1 '-pyrano [3,4] b) indole] -4-amine in the form of a physiologically acceptable acid addition salt, in particular the hydrochloride, hemicitrate or maleate salt, and the second pharmacologically active ingredient is duloxetine, preferably in the form of the hydrochloride addition salt.

In a still further preferred embodiment, the first pharmacologically active ingredient is (lr, 4r) -6'-fluoro-N, N-dimethyl-4-phenyl-, 9'-dihydro-3'H-spiro- [cyclohexan- 1,1 '-pirano [3,, b] indol] -4-amine in the form of the free base, ie the compound according to formula (I), and the second pharmacologically active ingredient is reboxetine, preferably in the form of the free compound.

In another preferred embodiment, the first pharmacologically active ingredient is (lr, 4r) -6'-fluoro-N, N-dimethyl-4-phenyl-4 ', 9'-dihydro-3'H-spiro- [cyclohexan-1 , 1'-pyran [3, 4, b] indole] -4-amine in the form of a physiologically acceptable acid addition salt, in particular the hydrochloride, hemicitrate or maleate salt, and the second pharmacologically active ingredient is reboxetine, preferably in the form of the free compound.

Another aspect of the invention relates to a pharmaceutical dosage form comprising the pharmaceutical composition according to the invention.

The first and second pharmacologically active ingredients are typically contained in the pharmaceutical dosage form according to the invention in a therapeutically effective amount. The amount that constitutes a therapeutically effective amount varies according to the pharmacologically active ingredients, the condition being treated, the severity of the condition, the patient being treated, and whether the pharmaceutical dosage form is designed for immediate release. or controlled.

In a preferred embodiment, the content of the first pharmacologically active ingredient in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, is at most 10% by weight or at most 5% by weight or at most 3% by weight or at most 1.0% by weight, more preferably at most 0.8% by weight, even more preferably at most 0.5% by weight, still more preferably at most 0.2% by weight, even more preferably at most 0.1% by weight, more preferably at most 0.05% by weight, and in particular at most 0.01% by weight or at most 0.005% by weight or at most 0.001% by weight.

In another preferred embodiment, the content of the second pharmacologically active ingredient in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, is at most 95% by weight, more preferably at most 80% by weight. % by weight, even more preferably at most 70% by weight, still more preferably at most 60% by weight, even more preferably at most 55% by weight, more preferably at most 50% by weight, and in particular at most 45% by weight.

In yet another preferred embodiment, the content of the first pharmacologically active ingredient in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, is at least 0.0001% by weight, more preferably at least 0.0003% by weight, even more preferably at least 0.0005% by weight, still more preferably at least 0.0008% by weight, even more preferably at least 0.001% by weight, more preferably at least 0.003% by weight and in particular at least 0.005% by weight.

In yet another preferred embodiment, the content of the second pharmacologically active ingredient in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, is at least 0.001% by weight, more preferably at least 0.003% by weight, even more preferably at least 0.005% by weight, still more preferably at least 0.001% by weight, even more preferably at least 0.1% by weight, more preferably at least 0.3% by weight, and in particular at least 0.5% by weight. weight.

In a further preferred embodiment, the content of the second pharmacologically active ingredient in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, is at least 0.1% by weight, more preferably at least 0.5% by weight, even more preferably at least 1% by weight, still more preferably at least 3% by weight, even more preferably at least 5% by weight, more preferably at least 7.5% by weight, and in particular at least 10% by weight.

Unless explicitly stated otherwise, in the meaning of the invention the indication "% by weight" will mean the weight of the respective ingredient by the total weight of the pharmaceutical dosage form or by the total weight of the pharmaceutical composition. , respectively.

Preferably, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range from 1: 1 to 1. : 100,000,000, more preferably 1: 1 to 1: 500,000, more preferably 1: 2 to 1: 100,000 and in particular 1:50 to 1: 100,000.

In a preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition in accordance with invention, respectively, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range of from 1: 1 to 1:10, more preferably 1: 2 to 1: 7 and more preferably 1: 3 to 1: 6 In still another preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range of from 1 : 10 to 1: 100, more preferably 1:20 to 1:85, still more preferably 1:30 to 1:75, more preferably 1:35 to 1:65, and in particular 1:40 to 1:60.

In still another preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range of from 1 : 10 to 1: 500, more preferably 1:30 to 1: 400, still more preferably 1:50 to 1: 250, more preferably 1:70 to 1: 150, and in particular 1:80 to 1: 120.

In a further preferred embodiment, in the form of pharmaceutical dosage according to the invention and the pharmaceutical composition according to the invention, respectively, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range from 1: 100 to 1: 10,000, more preferably 1: 200 to 1: 7,500, still more preferably 1: 500 to 1: 5,000, more preferably 1: 750 to 1: 2,500, and in particular 1: 900 to 1: 2,000.

In a further preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range of 1 : 1,000 to 1: 100,000, more preferably 1: 2,000 to 1: 80,000, still more preferably 1: 4,000 to 1: 50,000, even more preferably 1: 6,000 to 1: 20,000, more preferably 1: 8,000 to 1: 15,000 and in particular 1: 9,000 to 1: 12,500.

In still a further preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range of from 1: 5,000 to 1: 500,000, more preferably 1: 10,000 to 1: 400,000, still more preferably 1: 20,000 to 1: 300,000, more preferably 1: 40,000 to 1: 250,000, and in particular 1: 50,000 to 1: 200,000.

In yet a further preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range of 1: 100,000 to 1: 900,000, more preferably 1: 250,000 to 1: 800,000, still more preferably 1: 300,000 to 1: 700,000, more preferably 1: 350,000 to 1: 650,000, and in particular 1: 400,000 to 1: 600, 000 In a further preferred embodiment, in the pharmaceutical cosification form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range from 1 : 100,000 to 1: 1,000,000, more preferably 1: 250,000 to 1: 980,000, even more preferably 1: 500,000 to 1: 960,000, more preferably 1: 600,000 to 1: 950,000, and in particular 1: 700,000 to 1: 900, 000.

Preferably, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range from 1: 1 to 1: 1,000,000, more preferably 1: 1 to 1: 500,000, more preferably 1: 2 to 1: 100,000 and in particular 1:50 to 1: 100,000.

In a preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range of 1: 1. at 1:10, more preferably 1: 2 to 1: 7, and more preferably 1: 3 to 1: 6.

In another preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range from 1:10 to 1: 100, more preferably 1:20 to 1:85, still more preferably 1:30 to 1:75, more preferably 1:35 to 1:65, and in particular 1:40 to 1:60.

In yet another preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range of 1: 10 to 1: 500, more preferably 1:30 to 1: 400, still more preferably 1:50 to 1: 250, more preferably 1:70 to 1: 150, and in particular 1:80 to 1: 120.

In yet another preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range of 1: 100 to 1: 10,000, more preferably 1: 200 to 1: 7,500, still more preferably 1: 500 to 1: 5,000, more preferably 1: 750 to 1: 2,500, and in particular 1: 900 to 1: 1,200.

In a further preferred embodiment, in the form of pharmaceutical dosage according to the invention and the pharmaceutical composition according to the invention, respectively, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range from 1: 1,000 to 1: 100,000, more preferably 1 : 2,000 to 1: 80,000, still more preferably 1: 4,000 to 1: 50,000, even more preferably 1: 6,000 to 1: 20,000, more preferably 1: 8,000 to 1: 15,000, and in particular 1: 9,000 to 1: 12,500.

In still a further preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range of from 1 : 5,000 to 1: 500,000, more preferably 1: 10,000 to 1: 400,000, still more preferably 1: 20,000 to 1: 300,000, more preferably 1: 40,000 to 1: 250,000, and in particular 1: 50,000 to 1: 200, 000 .

In yet a further preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range of from 1: 100,000 to 1: 900,000, more preferably 1: 250,000 to 1: 800,000, still more preferably 1: 300,000 to 1: 700,000, more preferably 1: 350,000 a 1: 650,000, and in particular 1: 400,000 to 1: 600, 000.

In another preferred embodiment, in the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, the relative molar ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range of 1: 100,000. to 1: 1,000,000, more preferably 1: 250,000 to 1: 980,000, still more preferably 1: 500,000 to 1: 960,000, more preferably 1: 600,000 to 1: 950,000, and in particular 1: 700,000 to 1: 900, 000.

The amounts of the first and second pharmacologically active ingredient contained in the pharmaceutical dosage form according to the invention may vary depending on various factors well known to those skilled in the art, for example, the weight of the patient, the route of administration, the severity of the disease and the like.

In general, both pharmacologically active ingredients contained in the pharmaceutical dosage form according to the invention can be administered in amounts up to their maximum daily dose, which is known to those skilled in the art. For example, as the second pharmacologically active ingredient, duloxetine can preferably be administered to a patient in a maximum daily dose of up to 120 mg, and reboxetine can preferably be administered to a patient in a daily dose of up to 12 mg.

When administered in the prescribed manner, for example once daily or twice daily, the pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, preferably contain the first and the second pharmacologically active ingredient. , independently of one another, in an amount corresponding to 75 + 15% by weight, 75 ± 10% by weight, 75 + 5% by weight, 50 ± 15% by weight, 50 ± 10% by weight, 50 ± 5% % by weight, 25 ± 15% by weight, 25 ± 10% by weight or 25 ± 5% by weight of the respective maximum daily dose of the first and second pharmacologically active ingredient, respectively.

Preferably, the dosage form The pharmaceutical composition according to the invention contains the first pharmacologically active ingredient in a dose from 0.1 μg to 5,000 μg, more preferably 0.1 to 2,500 μg, still more preferably 1.0 g to 1,000 μg, even more preferably 10 to 800 μg, more preferably 15 μg a 600 μg, and in particular from 20 μg to 440 μ ?.

In a preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 13 ± 12 μg, more preferably 13 ± 10 μg, still more preferably 13 ± 8 μg, furthermore preferably 13 + 6 μg, still more preferably 13 + 5 μg, more preferably 13 + 4 μg, and in particular 13 ± 3 μg.

In another preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 20 ± 15 μg, more preferably 20 ± 13 μg, still more preferably 20 ± 12 μg, even more preferably 20 ± 10 μg, even more preferably 20 ± 8 μg, more preferably 20 + 6 μg, and in particular 20 ± 5 μg.

In still another preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose in the range of 40 ± 35 μg, more preferably 40 ± 30 μg, still more preferably 40 ± 25 μg, still more preferably 40 ± 20 μg, even more preferably 40 + 15 μg, more preferably 40 ± 10 μg, and in particular 40 + 5 μg.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 60 ± 50 μg, more preferably 60 + 40 μg, still more preferably 60 + 30 μg, still more preferably 60 ± 20 μg, more preferably 60 ± 10 μg, and in particular 60 + 5 g.

In a further preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 80 + 70 μg, more preferably 80 ± 60 μg, still more preferably 80 ± 50 μg, still more preferably 80 ± 40 μg, even more preferably 80 + 20 μg, more preferably 80 + 10 μg, and in particular 80 ± 5 μg.

In yet a further preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 100 ± 90 μg, more preferably 100 ± 80 μg, still more preferably 100 + 60 μg, still more preferably 100 ± 40 μg, still more preferably 100 ± 20 μ ?, more preferably 100 ± 10 μ ^, and in particular 100 ± 5 μ.

In yet a further preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 120 ± 100 μg, more preferably 120 ± 80 μg, still more preferably 120 ± 60 μg, even more preferably 120 ± 40 μg, still more preferably 120 ± 20 μg, more preferably 120 ± 10 μg, and in particular 120 ± 5 In another preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 150 ± 90 μg, more preferably 150 ± 80 μg, still more preferably 150 ± 60 μg, even more preferably 150 ± 40 μg, still more preferably 150 ± 20 μg, more preferably 150 ± 10 μg, and in particular 150 ± 5 μg.

In still another preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 170 ± 130 g, more preferably 170 ± 100 μg, still more preferably 170 ± 80 μg, still more preferably 170 + 60 μg, still more preferably 170 + 40 μg, more preferably 170 ± 20 μg, and in particular 170 ± 10 μg.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 200 ± 175 μg, more preferably 200 ± 150 μg, still more preferably 200 ± 125 μg, still more preferably 200 ± 100 μg, even more preferably 200 ± 75 μg, more preferably 200 ± 50 μg, and in particular 200 ± 25 μg.

In a further preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 400 ± 350 μqf more preferably 400 ± 300 μg, still more preferably 400 ± 250 μ, even more preferably 400 ± 200 μ, still more preferably 400 ± 150 μg, more preferably 400 + 100 μg, and in particular 400 ± 50 μg.

In another preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 600 ± 400 μg, more preferably 600 + 300 μg, still more preferably 600 + 250 μ ?, even more preferably 600 ± 200 μ ?, even more preferably 600 ± 150 μ ?, more preferably 600 ± 100 g, and in particular 600 ± 50 μg.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 800 + 550 μg, more preferably 800 ± 400 μg, still more preferably 800 ± 350 μg, even more preferably 800 ± 250 μg, even more preferably 800 ± 150 μg, more preferably 800 ± 100 μg, and in particular 800 ± 50 μg.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 1,000 ± 800 μg, more preferably 1,000 ± 600 μg, still more preferably 1,000 ± 500 μg, still more preferably 1,000 ± 300 μg, even more preferably 1,000 + 200 μg, more preferably 1,000 ± 100 μqr and in particular 1,000 ± 50 μg.

In a further preferred embodiment, the pharmaceutical dosage form according to the invention contains the first pharmacologically active ingredient in a dose within the range of 1,200 ± 1,000 μg, more preferably 1,200 ± 800 μg, still more preferably 1,200 ± 600 g, even more preferably 1,200 ± 400 μg, still more preferably 1,200 ± 200 μg, more preferably 1,200 ± 100 μg, and in particular 1, 200 ± 50 μg.

Preferably, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose from 1 mg to 1,000 mg, more preferably 2 mg to 800 mg, still more preferably 3 mg to 700 mg, more preferably 4 mg a 600 mg, and in particular from 5 mg to 500 mg.

In a preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 5 ± 4 mg, more preferably 5 ± 3 mg and more preferably 5 + 2 mg.

In another preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 10 ± 8 mg, more preferably 10 + 7 mg, still more preferably 10 + 6 mg, even more preferably 10 ± 5 mg and more preferably 10 ± 4 mg.

In still another preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 20 + 15 mg, more preferably 20 ± 12 mg, still more preferably 20 ± 10 mg and more preferably 20 ± 8 mg.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 35 ± 20 mg, more preferably 35 ± 18 mg, still more preferably 35 ± 15 mg, still more preferably 35 ± 12 mg, even more preferably 35 ± 10 mg and more preferably 35 ± 8 mg.

In a further preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 50 ± 40 mg, more preferably 50 ± 35 mg, still more preferably 50 ± 30 mg, even more preferably 50 ± 25 mg, even more preferably 50 + 20 mg, more preferably 50 ± 15 mg, and in particular 50 ± 10 mg.

In still a further preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 75 ± 55 mg, more preferably 75 ± 45 mg, still more preferably 75 ± 35 mg, even more preferably 75 ± 25 mg and more preferably 75 ± 15 mg.

In even a further preferred embodiment, the The pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 100 ± 150 mg, more preferably 100 ± 120 mg, still more preferably 100 ± 100 mg, even more preferably 100 ± 80 mg, even more preferably 100 ± 60 mg, more preferably 100 + 40 mg, and in particular 100 ± 20 mg.

In another preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 150 ± 100 mg, more preferably 150 ± 80 mg, still more preferably 150 + 60 mg, even more preferably 150 ± 40 mg, more preferably 150 ± 30 mg and in particular 150 ± 25 mg.

In still another preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 200 ± 150 mg, more preferably 200 ± 130 mg, still more preferably 200 ± 110 mg, even more preferably 200 ± 90 mg, even more preferably 200 ± 70 mg, more preferably 200 ± 60 mg and in particular 200 ± 50 mg.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 250 ± 200 mg, more preferably 250 ± 180 mg, still more preferably 250 ± 150 mg, even more preferably 250 ± 125 mg, even more preferably 250 + 100 mg, more preferably 250 ± 75 mg and in particular 250 ± 50 mg.

In a preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 300 ± 250 mg, more preferably 300 ± 200 mg, still more preferably 300 ± 150 mg, even more preferably 300 ± 125 mg, even more preferably 300 ± 100 mg, more preferably 300 ± 75 mg and in particular 300 ± 50 mg.

In another preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 500 ± 400 mg, more preferably 500 ± 300 mg, still more preferably 500 ± 200 mg, even more preferably 500 ± 150 mg, even more preferably 500 ± 100 mg, more preferably 500 ± 75 mg and in particular 500 ± 50 mg.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 750 ± 500 mg, more preferably 750 + 400 mg, still more preferably 750 ± 250 mg, even more preferably 750 ± 100 mg, even more preferably 750 ± 75 mg, more preferably 750 ± 50 mg and in particular 750 ± 25 mg.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention contains the second pharmacologically active ingredient in a dose within the range of 1,000 ± 500 mg, more preferably 1,000 + 400 mg, still more preferably 1,000 ± 250 mg, even more preferably 1,000 ± 100 mg, even more preferably 1,000 ± 75 mg, more preferably 1,000 ± 50 mg and in particular 1,000 ± 25 mg.

In a preferred embodiment, the pharmaceutical dosage form contains duloxetine, preferably (S) -duloxetine as the second pharmacologically active ingredient in a dose within the range of 10 mg to 800 mg, more preferably in the range of 15 mg to 500 mg, even more preferably in the range of 20 mg to 400 mg, more preferably in the range of 30 mg to 300 mg, and in particular in the range of 40 mg to 200 mg.

In another preferred embodiment, the pharmaceutical dosage form contains reboxetine as the second pharmacologically active ingredient in a dose within the range of 1 mg to 20 mg, more preferably in the range of 2 mg to 18 mg, even more preferably in the range of 3 mg to 16 mg, more preferably in the range of 4 mg to 15 mg, and in particular in the range of 5 mg to 14 mg.

In the pharmaceutical dosage form according to the invention, the dose of the first pharmacologically active ingredient is preferably within the range from 1:20 to 20: 1 of the amount which is equivalent to the dosage of the second pharmacologically active ingredient. In this respect, "equieffective" preferably means the dosage that would be required to achieve the desired therapeutic effect equivalent when administered alone. A skilled person recognizes that when the desired therapeutic effect is an analgesic effect, the effective dosage is determined with respect to the analgesic properties of the first pharmacologically active ingredient and the second pharmacologically active ingredient.

For example, when the dose of the second pharmacologically active ingredient, which is contained in the pharmaceutical dosage form according to the invention, amounts to for example 30 mg and provides an analgesic effect E when administered alone at this dose, and when the equieficaz amount of the first pharmacologically active ingredient, ie the amount necessary to provide the same analgesic effect E when administered alone, would be for example 4 g, the dosage of the first pharmacologically active ingredient, which is contained in the pharmaceutical dosage form according to the invention, can vary from 0.2 μg (4 μg / 20) to 80 μg (20/4 μg).

In a preferred embodiment, the dose of the first pharmacologically active ingredient is within the range from 1:15 to 15: 1, preferably within the range from 1:10 to 10: 1, more preferably within the range from 1: 8 to 8: 1, still more preferably within the range from 1: 6 to 6: 1, even more preferably within the range from 1: 4 to 4: 1, more preferably within the range from 1: 3 to 3: 1, and particularly preferably within the range from 1: 2 to 2: 1, of the amount that is equivalent to the dose of the second pharmacologically active ingredient.

Suitable routes of administration of the pharmaceutical dosage form according to the invention include but are not limited to oral, intravenous, intraperitoneal, intradermal, transdermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous, local and / or rectal administration.

In a preferred embodiment, the form of The pharmaceutical dosage according to the invention is for oral administration.

In another preferred embodiment, the pharmaceutical dosage form according to the invention is for parenteral administration, in particular intravenous, intraperitoneal, intrathecal, intramuscular or subcutaneous administration.

The pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, can be solid, semi-solid or liquid.

The pharmaceutical dosage form according to the invention and the pharmaceutical composition according to the invention, respectively, may contain auxiliary agents, for example, carriers, fillers, solvents, diluents, colorants and / or binders. The selection of auxiliary agents and the amounts thereof to be used depend, for example, on how the first and second pharmacologically active ingredient are to be administered, for example orally, intravenously, intraperitoneally, intradermally, transdermally, intrathecally, intramuscularly, intranasally, transmucosally, subcutaneously, rectally or locally.

Suitable auxiliary agents are in particular any substance known to a person skilled in the art useful for the preparation of galenical dosage forms. Examples of suitable auxiliary agents include but are not limited to: water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, starch. modified, gelatine, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinyl pyrrolidone, paraffins, waxes, natural and synthetic gums, acacia gum, alginates, dextran, fatty acids saturated and unsaturated, stearic acid, magnesium stearate, zinc stearate, glycerol stearate, sodium lauryl sulfate, edible oils, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and polypropylene fatty acid ester, sorbitan fatty acid ester, sorbic acid, benzoic acid, citric acid, ascorbic acid, tannic acid, chloride sodium, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, potash, phosphate of calcium, calcium dibasic phosphate, potassium bromide, iodide potassium, talc, kaolin, pectin, Crospovidone, agar and bentonite.

Pharmaceutical dosage forms that are suitable for oral administration include but are not limited to tablets, effervescent tablets, chewable tablets, dragees, capsules, drops, liquors and syrups. The oral pharmaceutical dosage forms can also be in the form of multiparticulates such as granules, pellets, spheres, crystals and the like, optionally compressed in a tablet, deposited in a capsule, deposited in a sachet or suspended in a suitable liquid medium. Oral pharmaceutical dosage forms may also be equipped with an enteric coating.

Pharmaceutical dosage forms that are suitable for parenteral, topical and inhalation administration include but are not limited to solutions, suspensions, dry preparations that can be easily reconstituted and aerosols.

Suppositories are a pharmaceutical dosage form suitable for rectal administration. Dosage forms in a reservoir, in dissolved form, for example, in a patch optionally with the addition of agents to promote skin penetration, are examples of suitable dosage forms for percutaneous administration.

In an especially preferred embodiment, the pharmaceutical dosage form according to the invention is a tablet.

In a preferred embodiment, the pharmaceutical dosage form according to the invention is for administration six times daily, five times daily, four times daily, three times daily, twice daily, once daily, or less frequently.

In another preferred embodiment, the pharmaceutical dosage form according to the invention is adapted for administration less frequently than once daily, preferably three times for four days (3/4), twice for three days (2/3), three times for five days (3/5), once for two days (1/2), three times a week (3/7), twice for five days (2/5), once for three days ( 1/3), twice a week (2/7), once for four days (1/4), once for five days (1/5), once for six days (1/6), or once in a week (1/7). According to this embodiment, administration once for two days (1/2) is particularly preferred.

In still another preferred embodiment, the pharmaceutical dosage form according to the invention It is for administration once daily.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention is for administration twice daily.

In a further preferred embodiment, the pharmaceutical dosage form according to the invention is for administration three times daily.

In yet a further preferred embodiment, the pharmaceutical dosage form according to the invention is for administration less frequently than once daily, preferably three times for five days (3/5) or once for two days (1/2) .

Particularly when the second pharmacologically active ingredient is duloxetine or reboxetine, the pharmaceutical dosage form according to the invention is preferably for administration once, twice or three times daily.

For the purpose of the specification, "administration three times daily" (tid) preferably means that the pharmaceutical dosage form according to the invention is adapted to be administered consecutively according to a regimen comprising the administration of three pharmaceutical dosage forms. per day, where the time interval between the consecutive administration of two dosage forms The pharmaceutical is at least 3 hours, preferably at least 4 hours, more preferably not less than 6 hours and in particular, approximately 8 hours.

For the purpose of the specification, "administration twice daily" (bid) preferably means that the pharmaceutical dosage form according to the invention is adapted to be administered consecutively according to a regimen comprising the administration of two pharmaceutical dosage forms per day, wherein the time interval between the consecutive administration of two pharmaceutical dosage forms is at least 6 hours, preferably at least 8 hours, more preferably at least 10 hours and in particular, approximately 12 hours.

For the purpose of the specification"administration once daily" (sid) preferably means that the pharmaceutical dosage form according to the invention is adapted to be administered consecutively according to a regimen comprising the administration of a pharmaceutical dosage form per day, wherein the The time interval between the consecutive administration of two pharmaceutical dosage forms is at least 18 hours, preferably at least 20 hours, more preferably at least 22 hours and in particular, approximately 24 hours.

An expert is fully aware that the administration regimens described above can be performed by administering an individual pharmaceutical dosage form containing the total amount of the first pharmacologically active ingredient and the total amount of the second pharmacologically active ingredient to be administered in a particular time point or, alternatively, administer a multitude of dosage units, i.e. two, three or more dosage units, the sum of the multitude of dosage units containing the total amount of the first pharmacologically active ingredient and the second ingredient pharmacologically active agents that are to be administered at the particular time point, wherein the individual dosage units are adapted for simultaneous administration or administration within a short period of time, for example within 5, 10 or 15 minutes.

In the following, the dose of the first and the second pharmacologically active ingredient are expressed according to the number of administrations prescribed "n" per day, ie, the number of administrations of the pharmaceutical dosage form according to the invention in the 24 hour course. As an example, 100 / n μg in case of administration once daily (n = 1) corresponds to a dose of 100 μg, and 100 / n μg in case of administration twice daily (n = 2) corresponds to a dose of 50 μg.

In a preferred embodiment, the pharmaceutical dosage form according to the invention is for administration less frequently than once daily (n = 3/4, 2/3, 3/5 or 1/2), wherein the dosage form Pharmaceutical contains the first pharmacologically active ingredient in a dose from 15 / n to 100 / n μg, preferably 20 / n to 80 / n μg, and the second pharmacologically active ingredient in a dose from 1 / n to 1,000 / n μg. According to this embodiment, the pharmaceutical dosage form according to the invention is preferably for oral administration, preferably in the form of a tablet.

In another preferred embodiment, the pharmaceutical dosage form according to the invention is for administration once daily (n = 1), wherein the pharmaceutical dosage form contains the first pharmacologically active ingredient in a dose from 15 / to 100 / n μg, preferably 20 / n to 80 / n μg, and the second pharmacologically active ingredient in a dose from 1 / n to 1, 000 / n mg. According to this embodiment, the pharmaceutical dosage form according to the invention is preferably for oral administration, preferably in the form of a tablet.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention is for multiple administration daily (n = 2, 3, 4, 5 or 6), wherein the pharmaceutical dosage form contains the first pharmacologically active ingredient in a doses from 15 / to 100 / n μg, preferably 20 / to 80 / ng, and the second pharmacologically active ingredient in a dose from 1 / n to 1, 000 / n mg. According to this embodiment, the pharmaceutical dosage form according to the invention is preferably for oral administration, preferably in the form of a tablet.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention is for administration less frequently than once daily (n = 3/4, 2/3, 3/5 or 1/2), wherein the form of Pharmaceutical dosage contains the first pharmacologically active ingredient in a dose from 150 / to 1,200 / n μg, preferably 200 / n to 800 / n μg, and the second pharmacologically active ingredient in a dose from 1 / n to 1,000 / n μq. According to this embodiment, the pharmaceutical dosage form according to the invention is preferably for oral administration, preferably in the form of a tablet.

In a further preferred embodiment, the pharmaceutical dosage form according to the invention is for administration once daily (n = 1), wherein the pharmaceutical dosage form contains the first pharmacologically active ingredient in a dose from 150 / to 1,200 / n μg, preferably 200 / n to 800 / n μg, and the second pharmacologically active ingredient in a dose from 1 / n to 1,000 / n mg. According to this embodiment, the pharmaceutical dosage form according to the invention is preferably for oral administration, preferably in the form of a tablet.

In still a preferred embodiment, the pharmaceutical dosage form according to the invention is for multiple administration daily (n = 2, 3, 4, 5 or 6), wherein the pharmaceutical dosage form contains the first pharmacologically active ingredient in a doses from 150 / n to 1,000 / n μg, preferably 200 / n to 800 / n μg, and the second pharmacologically active ingredient in a dose from 1 / n to 1,000 / n mg. According to this embodiment, the pharmaceutical dosage form according to the invention is preferably for oral administration, preferably in the form of a tablet.

The pharmaceutical dosage form of according to the invention can provide under in vitro conditions the immediate release or controlled release of the first pharmacologically active ingredient and / or the second pharmacologically active ingredient. The in vitro release is preferably determined according to Ph. Eur., Preferably the paddle paddle method, 75 rpm, 37 ° C, 900 ml of artificial gastric juice, pH 6.8.

The first pharmacologically active ingredient and / or the second pharmacologically active ingredient can independently of one another be present in the pharmaceutical dosage form at least partially in the controlled dosage form. For example, the first pharmacologically active ingredient and / or the second pharmacologically active ingredient can be released from the pharmaceutical dosage form in a prolonged manner, for example if administered orally, rectally or percutaneously. Such pharmaceutical dosage forms are particularly useful for the preparations "once daily" or "twice daily", which only have to be taken once a day, or twice a day, respectively. Suitable materials for controlled release are well known to those skilled in the art.

The pharmaceutical dosage form of In accordance with the invention providing the controlled release of the first pharmacologically active ingredient and / or the second pharmacologically active ingredient can be produced using materials, means, devices and processes which are well known in the prior art of pharmaceutical dosage forms.

To obtain a solid pharmaceutical dosage form such as a tablet, for example, the pharmacologically active ingredients of the pharmaceutical composition can be granulated with a pharmaceutical carrier, for example conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, magnesium stearate, calcium dibasic phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, for example water, to form a solid composition containing the pharmacologically active ingredients in a homogeneous distribution. The term "homogeneous distribution" is taken to mean that the pharmacologically active ingredients are evenly distributed over the entire composition, so that the composition can easily be divided into equally effective dosage units, such as tablets, pills or capsules and the like. The solid composition is then divided into dosage units. The tablets or pills of the pharmaceutical composition of according to the invention can also be coated or compounded in a different manner, to provide a dosage form with a controlled release.

If one of the pharmacologically active ingredients is to be released before the other pharmacologically active ingredient, for example at least 30 minutes or 1 hour in advance, pharmaceutical dosage forms having a corresponding release profile can be prepared. An example of such a pharmaceutical dosage form is an osmotically driven delivery system for achieving a delayed release of either the first or the second pharmacologically active ingredient from an internal (core) portion of the pharmaceutical dosage form via a coating that contains itself same the other pharmacologically active ingredient, which is consequently released before. In a delivery system of this kind, which is particularly suitable for oral administration, at least part, and preferably all, of the surface of the delivery system, preferably those parts to be brought into contact with the delivery means, is / are semipermeable, preferably equipped with a semipermeable coating, so that the surface (s) is / are permeable to the medium of release, but substantially, preferably entirely, impervious to the pharmacologically active ingredient contained in the core, the surface or and / or optionally the coating comprising at least one opening for releasing the pharmacologically active ingredient contained in the core. On the other hand, precisely that or those surfaces that are / are in contact with the release means are / are provided with a coating that contains and releases the other pharmacologically active ingredient. This is preferably taken to mean a system in the form of a tablet comprising a release opening, a core containing the first or second pharmacologically active ingredient, a portion of polymer that presses with the increase in volume, a semipermeable membrane and a coating that contains the other pharmacologically active ingredient. The embodiments and examples of osmotically driven delivery systems are, for example, described in U.S. Pat. 4,765,989, 4,783,337 and 4,612,008.

A further example of a suitable pharmaceutical dosage form is a gel matrix tablet. Suitable examples are provided in U.S. Pat. 4,389,393, 5,330,761, 5,399,362, 5,472,711 and 5,455,046. Particularly suitable is a form of dosage of delay matrix, with a non-homogeneous distribution of the pharmaceutical composition, with which, for example, a pharmacologically active ingredient, ie the first or the second pharmacologically active ingredient, is distributed in the outer region (the portion that is contact with the release medium more rapidly) of the matrix and the other pharmacologically active ingredient is distributed within the matrix. Upon contact with the release medium, the outer layer of the matrix initially (and rapidly) increases in volume and releases the pharmacologically active ingredient contained therein, followed by the significantly (more) controlled release of the other pharmacologically active ingredient. active. Examples of a suitable matrix include matrices with 1 to 80% by weight of one or more hydrophobic or hydrophobic polymers as pharmaceutically acceptable matrix formers.

Preferably, the pharmaceutical dosage form according to the invention provides an immediate release of the first pharmacologically active ingredient and the immediate or controlled release of the second pharmacologically active ingredient.

In a preferred embodiment, the pharmaceutical dosage form according to the invention it provides immediate release of both the first and the second pharmacologically active ingredients. In this particular case, a multiple administration daily, in particular an administration twice daily, three times daily, or up to six times a day is preferred.

In another preferred embodiment, the pharmaceutical dosage form according to the invention provides immediate release of the first pharmacologically active ingredient, and controlled release of the second pharmacologically active ingredient. This release profile can be achieved by employing the aforementioned methods, for example the osmotically driven delivery system that provides the first pharmacologically active ingredient in the coating and the second pharmacologically active ingredient in the core, or the delayed matrix dosage form. which contains the first pharmacologically active ingredient in the outer layer of the matrix and the second pharmacologically active ingredient in the inner part of the matrix.

In yet another preferred embodiment, the pharmaceutical dosage form according to the invention provides for the controlled release of both the first and second pharmacologically active ingredients.

In a further aspect, the invention relates to the use of the pharmaceutical composition according to the invention, and the pharmaceutical dosage form according to the invention respectively, in the prevention or treatment of pain, mood disorders and anxiety.

In a preferred embodiment, the pharmaceutical composition according to the invention and the pharmaceutical dosage form according to the invention, respectively, are for use in the treatment of pain, wherein the pain is preferably: - peripheral, central or skeletal muscle pain; I - acute, subacute or chronic pain; I - moderate to severe pain; I - neuropathic or psychogenic or nociceptive or mixed pain; I - lower back pain, visceral pain or headache; I Post-operative (post-surgical), cancer or inflammatory pain.

For the purpose of the specification, "acute pain" preferably refers to pain that lasts up to about 4 weeks, "subacute pain" preferably refers to pain that lasts from more than about 4 weeks to about 12 weeks, and "chronic pain". it preferably refers to pain that lasts for more than about 12 weeks.

Preferably, the pain is selected from the group consisting of cancer pain, peripheral neuropathic pain, osteoarthritis pain, chronic visceral pain, neuropathic pain (diabetic polyneuropathy, neuropathic pain associated with HIV, post-traumatic neuropathic pain, post-herpetic neuralgia, pain associated with chemotherapy), post-zosteric neuralgia, post-operative neuropathic pain, inflammatory pain, migraine, low back pain, fibromyalgia and trigeminal neuralgia.

In the following, the doses of the first and second pharmacologically active ingredients are again expressed according to the number of administrations "n" per day, ie the number of administrations of the pharmaceutical dosage form according to the invention in the 24 hour course.

In a preferred embodiment, the pharmaceutical dosage form is for use in the treatment of neuropathic pain, which may optionally be superimposed by nociceptive pain, wherein the dose of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably in the range from 1 / n μg to 800 / n μg or 1 / n μg to 600 / n μg or 1 / n μg to 400 / n μg or 1 / n iq to 250 / n μq, more preferably in the range of 5 / n μg to 150 / n μg, even more preferably in the range of 10 / n μg to 100 / n \ xq, more preferably in the range of 20 / n μg to 80 / n μg and in particular more preferably in the range of 30 / n μg to 50 / n μg. According to this embodiment, the dose of the second pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably in the range of 1 / n mg to 1,000 / n mg.

In a preferred embodiment, in particular when the pharmaceutical dosage form is for use in the treatment of neuropathic pain and the second pharmacologically active ingredient is duloxetine, preferably (S) -duloxetine, the dose of the first pharmacologically active ingredient contained in the form of Pharmaceutical dosage preferably is in the range of 1 / n μg to 800 / ng / 1 / ng to 600 / ng 1 / ng to 400 / ng or 1 / ng to 250 / ng, more preferably in the range of 5 / n μg to 150 / n μg, even more preferably in the range of 10 / n μg to 100 / n μg, more preferably in the range of 20 / n μg to 80 / n μg and particularly more preferably in the range from 30 / n μg to 50 / n μg; and the dose of the second pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably in the range of 10 / n mg to 300 / n mg, more preferably in the range of 15 / n mg to 250 / n mg, even more preferably in the range of 20 / n mg to 200 / n mg, more preferably in the range of 25 / n mg to 150 / n mg, and in particular in the range of 30 / n mg to 130 / n mg.

In another preferred embodiment, particularly when the pharmaceutical dosage form is for use in the treatment of neuropathic pain and the second pharmacologically active ingredient contained in the pharmaceutical dosage form is reboxetine, the dose of the first pharmacologically active ingredient preferably is in the range from 1 / nga 800 / n μg or 1 / n μg to 600 / n μg or 1 / n μg to 400 / n μg or 1 / n μg to 250 / n μg, more preferably in the range of 5 / n μg to 150 / n μg, even more preferably in the range of 10 / n μg to 100 / n μg, more preferably in the range of 20 / n μg to 80 / n μg and particularly more preferably in the range of 30 / n μg at 50 / n μg; and the dose of the second pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably in the range of 1 / n mg to 20 / n mg, more preferably in the range of 2 / n mg to 18 / n mg, more preferably in the range of the range from 3 / n mg to 16 / n mg and in particular in the range from 4 / n mg to 15 / n mg.

In still another preferred embodiment, the pharmaceutical dosage form is for use in the treatment of nociceptive pain, which may optionally be superimposed by neuropathic pain, wherein the dose of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably in the range of 50 / n ^ ig to 2,000 / n μq or 50 / n ^ ig to 1, 400 / n ( ^ go 50 / n μg to 1, 200 / n μg or 50 / n μg to 1, 000 / n μg, more preferably in the range of 100 / n μg to 800 / n iq, still more preferably in the range of 150 / n μg to 650 / n μg, even more preferably in the range of 250 / n μg to 550 / n μg and more preferably in the range of 350 / n μg to 450 / n μg According to this method, the dose of the second pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably in the range of 1 / n mg to 1, 000 / n mg.

In a preferred embodiment, particularly when the pharmaceutical dosage form is for use in the treatment of nociceptive pain and the second pharmacologically active ingredient is duloxetine, preferably (S) -duoxetine, the dose of the first pharmacologically active ingredient contained in the form of pharmaceutical dosage preferably is in the range of 50 / n μg to 2,000 / n μg or 50 / n μg to 1, 400 / n μg or 50 / n μg to 1,200 / n μg or 50 / n μg to 1,000 / n μg, more preferably in the range of 100 / n ^ ig to 800 / n μg, still more preferably in the range of 150 / n μg to 650 /? μ ?, even more preferably in the range of 250 / n μg to 550 / n μg and more preferably in the range of 350 / n μg to 450 / nμ ?, and the dose of the second pharmacologically active ingredient contained in the form of Pharmaceutical dosage preferably is in the range of 10 / n mg to 300 / n mg, more preferably in the range of 15 / n mg to 250 / n mg, even more preferably in the range of 20 / n mg to 200 / n mg , more preferably in the range of 25 / n mg to 150 mg, and in particular in the range of 30 / n mg to 130 mg.

In another preferred embodiment, particularly when the pharmaceutical dosage form is for use in the treatment of nociceptive pain and the second pharmacologically active ingredient is reboxetine, the dose of the first pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably in the range from 50 / n μg to 2,000 / n μg or 50 / n μg to 1,400 / n μg or 50 / n μg at 1, 200 / n μg or 50 / n μg at 1, 000 / n μg, more preferably in the range from 100 / n μg to 800 / n μg, still more preferably in the range of 150 / n μg to 650 / n μg, even more preferably in the range of 250 / n μg to 550 / n μg and more preferably in the range from 350 / n μg to 450 / n μg; and the dose of the second pharmacologically active ingredient contained in the pharmaceutical dosage form is preferably in the range of 1 / n mg to 20 / n mg, more preferably in the range of 2 / n mg to 18 / n mg, more preferably in the range of 3 / n mg to 16 / n mg and particularly in the range of 4 / n mg to 15 / n mg.

Preferably, the pharmaceutical composition contains the first and second pharmacologically active ingredients in a weight ratio such that they will exert a synergistic therapeutic effect with administration to a patient. By means of this, the term "synergistic therapeutic effect" may refer to a synergistic therapeutic effect with respect to the prevention or treatment of pain (synergistic analgesic effect), a synergistic therapeutic effect with respect to the prevention or treatment of anxiety. (anxiolytic synergistic effect), as well as a synergistic therapeutic effect with respect to the prevention or treatment of depression (synergistic antidepressant effect). Suitable weight ratios of the pharmacologically active ingredients that generate the synergistic therapeutic effect can be determined by methods well known to those skilled in the art.

A further aspect of the invention relates to a method for treating or preventing pain, anxiety or mood disorders comprising the preferred twice daily or once daily, preferably oral administration of the pharmaceutical dosage form according to the invention to a subject in need thereof.

In a particular preferred mode, the first pharmacologically active ingredient is (Ir, 4r) -6 '-fluoro-N, N-dimethyl-4-phenyl-4', 9 '-dihydro-3'? - spiro- [cyclohexan-1, -piran [3 , 4, b] indole] -4 -amine according to formula (I) in the form of its free base or a salt of hemicitrate, hydrochloride or maleate thereof; I the second pharmacologically active ingredient is duloxetine or reboxetine in the form of the free compound or the hydrochloride salt; I - the pharmaceutical composition and the pharmaceutical dosage form, respectively, contain the first pharmacologically active ingredient in a dose from 20 μg to 80 μ9 or from 80 μg to 200 μq or from 200 μg to 800 μg or from 800 μg to 1,200 μg; I - the pharmaceutical composition and the pharmaceutical dosage form, respectively, contain the second pharmacologically active ingredient in a dose from 1 mg to 1,000 mg, and / or the relative weight ratio of the first pharmacologically active ingredient to the second ingredient pharmacologically active is within the range of from 1: 1 to 1: 1,000,000, preferably 1: 2 to 1: 100,000 in the pharmaceutical composition and the pharmaceutical dosage form, respectively; I - the pharmaceutical composition is for use in the prevention or treatment of pain, anxiety or mood disorders; I the pharmaceutical composition is for use in the treatment of pain, wherein the pain is peripheral, central or skeletal muscle pain; and / or acute, subacute or chronic pain; and / or moderate to severe pain; and / or neuropathic or psychogenic or nociceptive or mixed pain; and / or lower back pain, visceral pain or headache; and / or post-operative (post-surgical), cancer or inflammatory pain; I - the pharmaceutical composition and the pharmaceutical dosage form, respectively, contain the first pharmacologically active ingredient and the second pharmacologically active ingredient in a weight ratio such that upon administration to a patient, they will exert a synergistic therapeutic effect; I The pharmaceutical dosage form provides immediate release of the first pharmacologically active ingredient in vitro according to Ph. Eur.; I the pharmaceutical dosage form provides immediate or controlled release of the second pharmacologically active ingredient in vitro according to Ph. Eur.; I the pharmaceutical dosage form is for oral administration; I the pharmaceutical dosage form is for administration once, twice or three times daily.

In a further aspect, the invention relates to a kit comprising a first pharmaceutical dosage form comprising the first pharmacologically active ingredient as described above, and a second pharmaceutical dosage form comprising the second pharmacologically active ingredient as described above. .

A suitable embodiment is a kit in which the first pharmaceutical dosage form comprising the first pharmacologically active ingredient and the second pharmaceutical dosage form comprising the second pharmacologically active ingredient, although spatially separated, are provided in a common form of presentation, for example a package.

Preferably, the first and second pharmaceutical dosage forms are adapted for simultaneous or sequential administration, wherein the first The pharmaceutical dosage form can be administered before or after the second pharmaceutical dosage form and wherein the first and second pharmaceutical dosage forms are administered either via the same or a different route of administration.

For the purposes of the specification, the term "simultaneous administration" preferably refers to an administration of the first and second pharmaceutical dosage forms within 15 minutes of each other, while the term "sequential administration" preferably refers to an administration of the first and second pharmaceutical dosage forms within a lapse of time of more than 15 minutes each other.

In a preferred embodiment, the first and second pharmaceutical dosage forms are adapted for administration to the patient via the same route.

In another preferred embodiment, the first and second pharmaceutical dosage forms are adapted for administration to the patient via different routes.

In a preferred embodiment, the first and second pharmaceutical dosage forms are administered simultaneously.

In another preferred embodiment, the first and second pharmaceutical dosage forms are administered sequentially In a preferred embodiment, the first and / or the second pharmaceutical dosage forms are adapted for administration less frequently than once daily.

In another preferred embodiment, the first and / or second pharmaceutical dosage forms are adapted for administration once daily.

In still another preferred embodiment, the first and / or the second pharmaceutical dosage forms are adapted for multiple administration daily, particularly twice daily or three times daily.

In a preferred embodiment, the first pharmaceutical dosage form is adapted for administration once daily and the second pharmaceutical dosage form is adapted for multiple administration on a daily basis, in particular administration twice daily or three times daily.

Suitable routes of administration of the pharmaceutical dosage forms contained in the kit include but are not limited to oral, intravenous, intraperitoneal, intradermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous and / or rectal administration.

In a preferred embodiment, one or both of the Pharmaceutical dosage forms contained in the kit are for oral administration.

In another preferred embodiment, one or both of the pharmaceutical dosage forms contained in the kit are for parenteral administration, in particular intravenous, intraperitoneal, intrathecal, intramuscular or subcutaneous administration.

In a preferred embodiment, the first and second pharmaceutical dosage forms are for oral, simultaneous administration less frequently than once daily.

In another preferred embodiment, the first and second pharmaceutical dosage forms are each for oral, sequential administration less frequently than once daily.

In still another preferred embodiment, the first and second pharmaceutical dosage forms are for sequential administration less frequently than once daily, wherein the first and second dosage dosage forms are adapted for administration via different routes, for example oral administration and parenteral In yet another preferred embodiment, the first and second pharmaceutical dosage forms are for oral, simultaneous administration once daily.

In a further preferred embodiment, the first and second pharmaceutical dosage forms are each for oral, sequential administration once daily.

In another preferred embodiment, the first and second pharmaceutical dosage forms are for sequential administration once daily each, wherein the first and second dosage dosage forms are adapted for administration via different routes, for example oral and parenteral administration.

In yet another preferred embodiment, the first and second pharmaceutical dosage forms are for oral, multiple simultaneous administration daily, in particular twice daily or three times daily.

In a further preferred embodiment, the first and second pharmaceutical dosage forms are each for oral, sequential multiple administration daily, in particular twice daily or three times daily.

In another preferred embodiment, the first and second pharmaceutical dosage forms are for multiple sequential administration each day, in particular twice daily or three times daily, wherein the first and second dosage dosage forms are adapted for administration via different routes, for example oral and parenteral administration.

The following examples further illustrate the invention but are not to be construed as limiting its scope.

Pharmacological Methods: In vivo experiments according to Chung In the following, all the amounts of the first pharmacologically active ingredient are specified as the hemicitrate salt.

As a second pharmacologically active ingredient, reboxetine and duloxetine were used.

Duloxetine was used in the form of (S) -enantiomer.

In the following, when the second pharmacologically active ingredient is (S) -duloxetine, all amounts are specified as the hydrochloride salt.

In the following, when the second pharmacologically active ingredient is reboxetine, all amounts are specified as the mesylate salt.

The weight ratios of the first and second pharmacologically active ingredient that will give rise to a supra-additive effect / synergistic effect can be determined in the Kim & Chung (Kim, S.H., Chung, J.M., An experimental model for peripheral mononeuropathy produced by ligature of the segmental spinal nerve in the rat. Pain 1992; 50: 355-63) as described in Schroder et al., Eur. J. Pain 2010, 14: 814. The references are incorporated herein by reference and form part of the description.

Ligatures were applied to the left spinal nerves L5 / L6 of male Sprague-Dawley rats (140-160 gr of body weight, Janvier, Genest St. Isle, France). The animals developed tactile allodynia in the ipsilateral leg. From one to four weeks after the operation, the threshold baseline (threshold of withdrawal) of tactile allodynia on the ipsilateral posterior leg and contralateral was measured by an electronic von Frey anesthesiometer (Somedic, Schweden). After the test and measurement of the baseline, the first pharmacologically active ingredient (Ir, 4r) -6 '-fluoro-N, -dimethyl-4-phenyl-4', 9 '-dihydro-3' H-spiro [cyclohexan-1, 1'-pyrano [3,4, b] indole] -4-amine in the form of the hemicitrate salt, and the second pharmacologically active ingredient according to the invention were each dissolved in a mixture of D SO (10%), Cremophor (5%) and glucose solution (85%) and injected intravenously (iv) (application volume 5 ml / kg). The first and second pharmacologically active ingredients were administered either as the individual substance respective or both at the same time. The animals were randomly assigned to groups of 10 for each dose and test vehicle (D SO (10%), Cremophor (5%) and glucose solution (85%)) and the tactile withdrawal thresholds were tested 0.5 hr before administration and at various time points (0.5, 1 and 3 hours) after intravenous injection. The ipsilateral and contralateral posterior legs were tested. The mean withdrawal threshold for each animal at a given time is calculated from five individual stimulations with von Frey's electronic filament. The withdrawal thresholds of the injured legs are expressed as% MPE (Maximum possible effect) by comparing the pre-drug threshold of the Chung Animals (= 0% MPE) and the control threshold of the Sham animals (100% MPE) . A cut is set at 100% MPE. The effect of each compound and vehicle is calculated for each time point of the test as an inter-individual% MPE value.

The data (anti-allodynic efficacy (% MPE), ipsilateral, leg withdrawal threshold, ipsilateral and contralateral) were analyzed by means of an analysis of variance (ANOVA) of two factors with repeated measurements. In case of a significant effect of the treatment, a post hoc analysis with Bonferroni adjustment was performed. The results were considered statistically significant yes p < 0.05.

Results: a) Duloxetine as the second pharmacologically active ingredient The first pharmacologically active ingredient (0.0316 μg / kg body weight i.v.) showed a threshold of withdrawal of the ipsilateral hind leg with an efficacy of 21.0% MPE in 30 minutes after administration.

The second pharmacologically active ingredient (0.100 mg / kg body weight i.v.) showed a threshold of withdrawal of the ipsilateral posterior leg with an efficacy of 25.3% MPE in 30 minutes after administration.

When administered as a combination, the first and second pharmacologically active ingredients were tested at a fixed ratio of 1: 3,164 (first to second pharmacologically active ingredient) in doses of 0.0316 μg / kg body weight + 0.100 mg / kg of body weight i. v. of the first and the second pharmacologically active ingredient, respectively. This combined administration of the first and second pharmacologically active ingredients resulted in a supra-additive increase in the threshold of withdrawal of the ipsilateral posterior leg compared to the administration of the individual pharmacologically active ingredients showing a synergistic effect with 54.7% MPE in 30 minutes after administration.

Figure 1 shows the% MPE depending on the time elapsed after administration.

• Vehicle (n = 10) ? First pharmacologically active ingredient (0.0316 g / kg, n = 10) T Second pharmacologically active ingredient (0.100 mg / kg, n = 10) Combination of the first and second pharmacologically active ingredients (0.0316 μg / kg + 0.100 mg / kg, n = 10) Theoretical additive value The experimental results demonstrating the supra-additive effects of the combination of the first and second pharmacologically active ingredients are summarized in the following Table 1.

Table 1: The MPE% (Maximum possible effect) of the first and second pharmacologically active ingredients and the combination of the first pharmacologically active: The experimental value of% MPE of 54.7 (30 minutes) in the case of the combined administration of the first and second pharmacologically active ingredients according to the invention is above the theoretical additive value of% MPE of the respective individual pharmacologically active ingredients. Thus, the interaction of the first and second ingredients pharmacologically active is synergistic.

The results of the statistical analysis of the experimental data are summarized in Table 2.

Table 2: Statistical evaluation of the data following the analysis of variance (ANOVA) of two factors and post hoc analysis with Bonferroni adjustment. p: Level of statistical significance.

As can be seen from Table 2, the results Experimental results are statistically significant (p <0.05). The synergistic effect of the first and second pharmacologically active ingredients according to the invention is verified by the Bonferroni adjustment which provides a value of p < 0.05.

Thus, the synergistic effects of the first and second pharmacologically active ingredients result in increased anti-nociceptive effects. b) Reboxetine as the second pharmacologically active ingredient The first pharmacologically active ingredient (0.0316 μg / kg body weight i.v.) showed a threshold of withdrawal of the ipsilateral posterior leg with an efficacy of 20.9% MPE in 30 minutes after administration.

The second pharmacologically active ingredient (0.316 mg / kg of body weight i.v.) showed a threshold of withdrawal of the ipsilateral posterior leg with an efficacy of 25.7% MPE in 30 minutes after administration.

When administered as a combination, the first and second pharmacologically active ingredients were tested at a fixed ratio of 1: 10,000 (first to second pharmacologically active ingredient) in doses of 0.0316 μg / kg body weight + 0.316 mg / kg of body weight i. v. of the first and the second pharmacologically active ingredient, respectively. This combined administration of the first and second pharmacologically active ingredients resulted in a threshold of withdrawal of the ipsilateral posterior leg of 34.4% MPE in 30 minutes after administration. None of the treatments resulted in a statistically significant increase in the paw withdrawal thresholds.

Figure 2 shows the% MPE depending on the time elapsed after administration.

Vehicle (n = 10) First pharmacologically active ingredient (0.0316 g / kg, n = 10) Second pharmacologically active ingredient (0.316 mg / kg, n = 10) O Combination of the first and second pharmacologically active ingredients (0.0316 pg / kg + 0.316 mg / kg, n = 10) Theoretical additive value The experimental results of the combination of the first and second pharmacologically active ingredients are summarized in the following Table 3.

Table 3: % MPE (Maximum possible effect) of the first and second pharmacologically active ingredients and the combination of the first and second pharmacologically active ingredients: The results of the statistical analysis of the experimental data are summarized in Table 4.

Table 4: Statistical evaluation of the data following the analysis of variance (ANOVA) of two factors and post hoc analysis with Bonferroni adjustment. p: Level of statistical significance.

Claims

1. Pharmaceutical composition characterized in that it comprises: a) A first pharmacologically active ingredient, selected from (Ir, 4 r) -6 '-fluoro-N, N-dimethyl-4-phenyl-4', 9 '-dihydro-3' H-spiro [cyclohexan-1, 1 '-pirano- [3, 4, b] -indol] -4-amine and the physiologically acceptable salts thereof, and b) A second pharmacologically active ingredient, which is an antidepressant.

2. Pharmaceutical composition according to claim 1, characterized in that the first pharmacologically active ingredient is (Ir, 4r) -6 '-fluoro-N, N-dimethyl-4-phenyl-4', 9 '-dihydro-3' H- spiro [cyclohexan-1,1'-pyrano [3,4, b] indole] -4-amine.

3. Pharmaceutical composition according to claims 1 or 2, characterized in that the second pharmacologically active ingredient is a selective inhibitor of serotonin reuptake.

4. Pharmaceutical composition according to claim 3, characterized in that the selective inhibitor of serotonin reuptake is selected from the group consisting of zimeldine, fluoxetine, citalopram, paroxetine, sertraline, alaproclate, fluvoxamine, etoperidone, escitalopram and the physiologically acceptable salts acceptable from them.

5. Pharmaceutical composition according to claim 1 or 2, characterized in that the second pharmacologically active ingredient is a non-selective inhibitor of serotonin reuptake.

6. Pharmaceutical composition according to claim 5, characterized in that the non-selective serotonin reuptake inhibitor is selected from the group consisting of desipramine, imipramine, imipramine oxide, clomipramine, opipramol, trimipramine, lofepramine, dibenzepine, amitriptyline, nortriptyline, protriptyline , doxepin, iprindol, melitracene, butryptilene, dosulepine, amoxapine, dimethacrine, amineptine, maprotiline, quinupramine and the physiologically acceptable salts thereof.

7. Pharmaceutical composition according to claim 1 or 2, characterized in that the second pharmacologically active ingredient is selected from the group consisting of oxitriptan, tryptophan, mianserin, nomifensin, trazodone, nefazodone, minaprine, bifemelane, viloxazine, oxafloxane, mirtazapine, bupropion, medifoxamine, thianeptine, pivagabine, venlafaxine, milnacipran, reboxetine, gepirone, duloxetine, agomelatine, desvenlafaxine, vilazodone and the physiologically acceptable salts thereof, as well as Hyperici herba.

8. Pharmaceutical composition according to any of the preceding claims, characterized in that it contains the first and second pharmacologically active ingredients in such a weight ratio that they will exert a synergistic therapeutic effect with their administration to a patient.

9. Pharmaceutical composition according to any of the preceding claims, characterized in that the relative weight ratio of the first pharmacologically active ingredient to the second pharmacologically active ingredient is within the range from 1: 1 to 1,000,000.

10. Pharmaceutical composition according to any of the preceding claims, characterized in that it is for use in the prevention or treatment of pain, anxiety or a mood disorder.

11. Pharmaceutical composition according to claim 10, characterized in that the pain is: - peripheral, central or skeletal muscle pain; I - acute, subacute or chronic pain; I - moderate to severe pain; I - neuropathic or psychogenic or nociceptive or mixed pain; I - lower back pain, visceral pain or headache; I Post-operative (post-surgical), cancer or inflammatory pain.

12. Pharmaceutical dosage form characterized in that it comprises the pharmaceutical composition according to any of the preceding claims.

13. Pharmaceutical dosage form according to claim 12, characterized in that it contains the first pharmacologically active ingredient in a dose from 10 to 1,200 μg.

14. Pharmaceutical dosage form according to claim 12 or 13, characterized in that it contains the second pharmacologically active ingredient in a dose from 1 mg to 1,000 mg.

15. Case characterized in that it comprises a first pharmaceutical dosage form comprising the first pharmacologically active ingredient according to claim 1 or 2, and a second pharmaceutical dosage form comprising the second pharmacologically active ingredient according to any of claims 1, 3, 4, 5, 6 or 7.